This study will investigate low-level viral loads in HIV-infected patients taking highly active antiretroviral therapy (HAART). Although HAART reduces viral levels and restores immune function to some degree, it does not cure HIV infection. The virus persists even at levels below that which it can be detected. This study will examine where this residual virus comes from in order to better understand the infection and the effectiveness of therapies. In addition, the study will 1) evaluate the ability of a new test to detect the virus at low levels; and 2) determine whether adding the protease inhibitor Kaletra to the HAART treatment regimen for patients with a low viral load will further decrease their viral load.

HIV-infected patients 18 years of age and older may be eligible for this study. Patients involved in the viral load test will be recruited from an NIAID HIV study in which they are already participating. Three groups of patients will be enrolled: those with a viral load of less than 50 copies/ml plasma, those with 51-500 copies/ml, and those with 501-5000 copies/ml. Patients involved in the Kaletra trial must have been taking HAART for 6 months or more and have less than 50 viral copies/ml plasma. They will be screened for this study with a history, physical examination, and routine laboratory tests.

Participants in the viral load test evaluation will donate 70 ml of blood up to four times. No more than one sample will be collected per day.

Participants in the Kaletra trial will have blood samples drawn on two successive days and will then be randomly assigned to one of two treatment groups. One group will begin Kaletra therapy (four capsules two times a day) immediately; the other will undergo observation for 4 weeks before starting Kaletra. Depending on what group they are in, patients will provide blood samples for viral load measurements and clinical samples according to the following schedule:

Immediate Kaletra

One sample each during weeks 1, 2, and 3, of therapy and two samples during week 4.

Delayed Kaletra

One sample each during weeks 1, 2, and 3 of observation and two samples during week 4. After starting therapy, one sample will be collected each week during weeks 1, 2, and 3 of therapy and two samples during week 4.

In both groups, after the last dose of medicine on day 28, Kaletra therapy will be complete. At the end of therapy, additional blood will be collected for viral sampling as follows: one sample each during weeks 1, 2, and 3, and two samples during week 4 after Kaletra therapy.

Further study details as provided by National Institutes of Health Clinical Center (CC):

Enrollment:

73

Study Start Date:

July 2002

Estimated Study Completion Date:

February 2013

Detailed Description:

This protocol is an exploratory study of HIV expression in patients who are receiving highly active antiviral therapy and who have low viral loads below or near the current limit of detection (50 copies/ml plasma). Recent studies have suggested that patients with suppressed viral loads in this low range have continued HIV expression, but the amount and the origin of this virus remains unknown. The amount of virus expression in plasma is uncertain because the current viral load assays are imprecise in the cutoff range of 50-75 copies/ml plasma. The origin of the HIV found at low viral loads detected is unknown as well; two possible sources of virus include expression from long-lived reservoirs of infected cells, and low level spreading infection to uninfected cells. Determining the origin of HIV expression has clinical importance; currently available HIV drug therapy will have little effect on HIV expression from established reservoirs, but more potent HIV therapy could potentially inhibit a spreading HIV infection.

In this study we plan two principal objectives. First, we will investigate the level of HIV expression in plasma samples at low viral loads using a new HIV load assay with enhanced sensitivity and precision in the viral load range of 1-100 copies. If data from the survey confirms acceptable performance characteristics for this assay we will proceed with stage II of the protocol. In stage II we plan to determine, in several short-term intensification approaches to investigate whether the incorporation of an additional antiretroviral to suppressive HAART regimens ("intensification HAART") will further suppress plasma virus. In a small pilot study, we will plan to intensify regimens for 30 days in a nonrandomized fashion. Secondly, we plan to study patients who are switching medications for preference or mild toxicity. In these patients we will intensify their regimens for 30 days in an overlap fashion, adding the new drug instead of switching medications. After 30 days of drug overlap, we will continue the new drug and discontinue the identified antiretroviral. These initial studies will assist in obtaining initial data and confirming the estimated sample size of a larger, randomized study to rigorously investigate the virologic effects of drug intensification. If these initial proof-of-concept experiments suggest that HIV may be suppressed by intensification HAART, then we plan to expand the study in a larger controlled trial to determine the degree of suppression possible with intensification therapy.

As a secondary objective we will investigate whether it is feasible to study HIV genetic variation in samples from patients with suppressed viral loads using molecular techniques developed to study HIV variation in patients with viral loads greater than 1000 copies/ml plasma (protocol 00-I-0110).

We plan to enroll up to 70 patients in a viral load survey cohort of HIV viral loads, and analyze a series of samples from completed trials of antiretroviral therapy.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA: VIRAL SURVEY COHORT

HIV-1 infection documented by HIV ELISA and WB

Age greater than or equal to 18 years old

Hemoglobin greater than or equal to 12 mg/dl within the last six weeks

Willingness to take an additional antiretroviral to current regimen for 30 days.

For patients to start lopinavir/ritonavir, willingness to reduce the dose of sildenafil and other co-administered medicines that may be affected by the addition of lopinavir/ritonavir during the course of therapy with lopinavir/ritonavir

For patients to start efavirenz arm, willingness to take efavirenz and adjust other medications or supplements as necessary, and to be aware that efavirenz is contraindicated in pregnancy and that may result in false positive urine tests for THC

For patients starting raltegravir, no prior history of rhabdomyolysis and no co-administration of agents which, in the opinion of the investigators, would cause rhabodomyolysis or myopathy.

Patient must have primary care outside this protocol.

Patients must practice accepted barrier methods to prevent pregnancy.

For patients enrolled in piolt study of suppression after development of resistance, patient must have documented evidence of prior drug resistance either: Prior resisteance testing with the presence of resisnce mutations or documents evidence of viral RNA levels greater than 100 copies/ml plasma for greater than 6 months despite antiretroviral thereapy. Patients with prior therapy on monotherapy or suboptimal combination therapy ARE eligible for this study.

Willingness to take an additional antiretroviral to current regimen for 30 days.

For patients to start lopinavir/ritonavir, willingness to reduce the dose of sildenafil and other co-administered medicines that may be affected by the addition of lopinavir/ritonavir during the course of therapy with lopinavir/ritonavir

For patients to start efavirenz arm, willingness to take efavirenz and adjust other medications or supplements as necessary, and to be aware that efavirenz is contraindicated in pregnancy and that may result in false positive urine tests for THC

Patient must have primary care outside this protocol.

Patients must practice accepted barrier methods to prevent pregnancy.

EXCLUSION CRITERIA:

Requirement for cytotoxic agents including hydroxyurea or vaccinations during the study period

Chronic corticosteroid therapy

Concurrent therapy with investigational cytokines including IL-2 or IL-12 during the course of the study. Prior administration of cytokines is not an exclusion criteria; at least 4 months from most recent cycle of IL-2 or IL-12. GCSF and erythropoietin therapy will be permitted

History of taking a salvage regimen; i.e., patient has had clinical resistance to antiretrovirals. Changing antiviral therapy because of adverse effects is permitted

Prior PI therapy or NNRTI therapy is not permitted unless the previous PI-containing therapy was switched because of patient preference. If the patient has a documented history of lipid elevations (fasting triglycerides greater than 750 mg/dl), the patient will not be eligible for PI addition.

Any febrile illness (T greater than 38.0 degrees C) in the 3 weeks prior to enrollment

Any vaccination in the 6 weeks prior to enrollment

Current pregnancy or lactation, history of pregnancy in the last 4 months

Willingness to take an additional antiretroviral to current regimen for 30 days

For patients planning to start lopinavir/ritonavir, or other ritonavir containing regimen willingness to reduce the dose of sildenafil and other co-administered medicines that may be affected by the addition of ritonavir during the course of therapy with lopinavir/ritonavir

For patients to start efavirenz, willingness to take efavirenz and adjust other medications or supplements as necessary, and to be aware that efavirenz is contraindicated in pregnancy and that may result in false positive urine tests for THC

Patient must have primary care outside this protocol

Patients must practice accepted barrier methods to prevent pregnancy.

EXCLUSION CRITERIA:

Requirement for cytotoxic agents including hydroxyurea or vaccinations during the study period

Chronic corticosteroid therapy

Concurrent therapy with investigational cytokines including IL-2 or IL-12 during the course of the study. Prior administration of cytokines is not an exclusion criteria; at least 4 months from most recent cycle of IL-2 or IL-12. GCSF and erythropoietin therapy will be permitted

History of taking a salvage regimen; i.e., patient has had clinical resistance to antiretrovirals. Changing antiviral therapy because of adverse effects is permitted

Prior PI therapy or NNRTI therapy is not permitted unless the previous PI-containing therapy was switched because of patient preference. If the patient has a documented history of lipid elevations (fasting triglycerides greater than 750 mg/dl) the patient will not be eligible for PI addition.

Any febrile illness (T greater than 38 degrees C) in the 3 weeks prior to enrollment

Any vaccination in the 6 weeks prior to enrollment

Current Pregnancy or lactation, history of pregnancy in the last 4 months

For patients who are adding ritonavir or efavirenz, concomitant use with drugs that are highly dependent on cytochrome P 450 for clearance, which, in the opinion of the investigators, may lead to the unexpected changes in their concentrations occurring after the new drug is added. Examples include but are not limited to: wafarin-like anticoagulation , amiodarone, astemizole, cisapride, statin class of drugs, gemfibrozil, cyclosporine, ergonavine, ergotamine, methylergonavine, dihydroergotamine, dofetilide, flecanide, quinidine, fusidic acid, methadone, demerol, midazolam, triazolam, phenytoin, dilantin, pimozide, sirolimus, tacrolimus, propafenone, quinupristin, terfenadine, theophylline, rifampin, rifapentene, or rifabutin and illicit substances, including the recreational substance (ecstasy) methylenedioxymethamphetamine

History of chronic diarrhea or inflammatory bowel disease

History of hemophilia

Inability to comply with the protocol

For those starting efavirenz, significant depression, which, in the opinion of the investigators, would be significantly worsened by efavirenz

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00043641